Weight gain on integrase inhibitor treatment was
first flagged up in late 2018 and, since the first reports, other research
groups have been looking at weight gain in a wider range of patient groups.

The form of weight gain seen in people starting integrase
inhibitor treatment is not the same as the fat redistribution syndrome, or lipodystrophy,
observed when the first generation of protease inhibitors was used in
combination with nucleoside reverse transcriptase inhibitors (NRTIs) or when
non-nucleoside reverse transcriptase inhibitors (NNRTIs) were used in combination with
older NRTIs, especially stavudine (d4T).

Body mass index, or BMI, is a measure of body size. It combines a person's weight with their height. The BMI gives an idea of whether a person has the correct weight for their height. Many BMI calculators can be found on the internet.

A group of diseases characterized by high levels of blood sugar (glucose). Type 1 diabetes occurs when the body fails to produce insulin, which is a hormone that regulates blood sugar. Type 2 diabetes occurs when the body either does not produce enough insulin or does not use insulin normally (insulin resistance). Common symptoms of diabetes include frequent urination, unusual thirst and extreme hunger. Some antiretroviral drugs may increase the risk of type 2 diabetes.

Whereas lipodystrophy involved accumulation of central
abdominal or visceral fat, and loss of subcutaneous fat, weight gain on modern
antiretroviral treatment consists of general fat gain – both subcutaneous and
central fat – with an increase in waist circumference.

Weight gain after starting antiretroviral treatment is a
common event; gaining a modest amount of weight is normal, especially in people
with more advanced HIV disease or low body mass prior to treatment. It’s been
dubbed 'return to health' weight gain.

However, what has been seen with some drug regimens – not
just integrase inhibitors, but some protease inhibitors too – is more
substantial weight gain. Some clinicians have raised concerns that weight gain
might eventually increase cardiovascular disease risks, blood pressure and type
2 diabetes in populations which already have a high prevalence of obesity and
other risk factors for cardiovascular disease. The VACS study showed that
gaining five pounds (2.26kg) after starting treatment increased the risk of
diabetes by 14%, while the D:A:D cohort found that every unit of body mass
increase after starting antiretroviral treatment raised the risk of diabetes by 13%.

But is this weight gain caused by antiretroviral drugs or is
it a product of environments that encourage people to eat unhealthily and be physically inactive? Moderating a discussion on weight
gain after starting treatment, Jane O’Halloran of Washington University, St
Louis, pointed out that up to half of adults starting antiretroviral therapy in
the United States may already be obese. Weight gain after starting treatment
may be occurring in adults who already have diets and lifestyles that
predispose them to further weight gain.

On the other hand, asked Carl Fichtenbaum of University of
Cincinatti, what if weight gain on regimens other than integrase inhibitors is being
blunted by effects of certain drugs on fat deposits?

Studies presented at CROI this week attempted to shed more
light on the problem, specifically: whether integrase inhibitors cause more
weight gain than other drugs; how much weight is being gained and over what
period; who might be at greater risk; and whether there is any difference
between integrase inhibitors.

Are integrase inhibitors associated with greater weight gain than other drugs?

The largest study to report on this question, the North
American AIDS Cohort Collaboration, found that among people starting treatment
for the first time, treatment with dolutegravir or raltegravir was associated
with greater weight gain than treatment with NNRTI-based treatment. The cohort
analysis looked at 24,001 people who started treatment between 2007 and 2015. During
that period, 4740 people started treatment with an integrase inhibitor (1681 raltegravir, 2124
elvitegravir and 935 dolutegravir).

After five years on treatment, people taking an integrase
inhibitor had gained a median of 6kg, compared to 4.3kg for people who started
an NNRTI (p < 0.001). There was no difference in weight gain between people
who started an integrase inhibitor or a protease inhibitor. (Bourgi)

The Women’s Interagency Health Study examined its cohort of
1118 women who had undetectable viral loads between 2008 and 2017 on treatment,
234 of whom switched to an integrase inhibitor during that period. This cohort
had a high prevalence of obesity and a mean body mass index of just over 30 at
baseline. There was no significant difference in body weight by demographics or
by drug regimen at baseline, with mean weight of approximately 80kg. Women who
switched to an integrase inhibitor gained 2.14kg more than women who did not
switch. (Kerchberger)

Dallas Parkland Hospital looked at 4048 patients who started treatment between 2009 and 2017, with median exposure to antiretroviral treatment of 6.7 years. They
looked at differences in changes in body mass index after starting treatment between
people who started regimens based on an NNRTI, a protease inhibitor or an integrase inhibitor.

The median increase in body mass index was greatest in the integrase
inhibitor group (+0.32/m2 per year) and smallest in the NNRTI group
(+0.22/mm2 per year). (Bedimo)

In summary, most studies did find an association between
integrase inhibitor treatment and weight gain, in previously untreated people
and in people switching from another regimen.

One study did not find an association. An analysis of clinic
databases in 21 US states, covering 3468 people with suppressed viral load for
at least one year, looked at weight gain between 2013 and 2018. They found that
patients gained an average of 3% a year in weight, but in a discussion on weight gain research Grace McComsey pointed
out that most people are not gaining substantial weight – “only 30% gained more
than 3%”.

Regression analysis failed to show an association between
integrase inhibitor treatment and weight gain. Instead, significant predictors
of weight gain in this population were low body mass index at baseline, being
overweight at baseline, hypogonadism (low testosterone), protease inhibitor
treatment, and psychiatric disorder. (McComsey)

The HIV prevention study HPTN 077 looked at weight gain in
199 HIV-negative people who received oral induction treatment and subsequent
injectable cabotegravir. Weight was measured at each study visit to week 41 and
no difference in weight gain was seen between those who received cabotegravir
or placebo – both groups gained around 1kg. The investigators commented that an
interaction between HIV infection and integrase inhibitor treatment may be an
important contributor to weight gain on antiretroviral treatment. (Landovitz)

Are some people at greater risk of weight gain on integrase inhibitor treatment?

A review of 972 people who switched to an integrase
inhibitor in AIDS Clinical Trials Group studies found that in the two years
after switching, white or black race, age 60 or over, or a pre-switching body mass index of
30 or above (obese) were associated with greater weight gain in women. In men,
only age over 60 was associated with weight gain. Dolutegravir was associated
with the greatest weight gain and the gains in weight after starting treatment were
larger than those expected for a person’s age. (Lake)

A review of 437 patients in the HIV Outpatients Study found
that among patients who switched to integrase inhibitor-based treatment after
viral suppression on another regimen, weight gain was significantly greater in
non-Hispanic black patients and in people with no prior history of nucleoside
reverse transcriptase inhibitor use. (Palella)

Are there differences between integrase inhibitors in weight gain?

In the NACCORD study, researchers looked at weight gain
after two years on each integrase inhibitor and compared this with weight
gained by people starting treatment with an NNRTI or a protease inhibitor.
Taking into account that fewer people received dolutegravir because it was
licensed after raltegravir and elvitegravir, the investigators found that
patients on raltegravir or dolutegravir gained significantly more weight than
people taking NNRTI treatment, while people taking elvitegravir gained less weight
than people taking a protease inhibitor.

In the Parkland study discussed in a previous section, women
gained more weight than men on dolutegravir and raltegravir, but not on
elvitegravir. Black people gained more than other ethnic groups on dolutegravir, but not
on other integrase inhibitors. In the entire cohort, people taking elvitegravir
gained more weight than people taking dolutegravir or raltegravir. (Bedimo)

In summary, no clear pattern emerged from the research
presented at CROI regarding the effects of various integrase inhibitors.

Dolutegravir is a preferred medication for treating HIV infection, but it recently has been linked to a 6- to 9-fold increase in the risk for neural tube defects among babies born to mothers receiving the drug during early gestation. Researchers at Baylor College of Medicine suspected that folic acid (vitamin B9), which is known to prevent the vast majority of neural tube defect cases, could be a part of the puzzle of dolutegravir’s negative side effects.

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